Semin Neurol 2022; 42(05): 583-593
DOI: 10.1055/a-1958-0802
Review Article

Long-Term Effects of Antiseizure Medications

1   Department of Neurology, Lewis Katz Temple School of Medicine, Philadelphia, Pennsylvania
› Author Affiliations

Abstract

Most patients with epilepsy will benefit from seizure control with one of an array of chronic antiseizure medications. Knowledge of the potential long-term effects of these medications is critical to prevent adverse consequences on overall health. Antiseizure medications vary in their capacities to affect the brain and peripheral nerves, hormones, bone mineralization, cardiovascular risk, renal health, hepatic, hematological, and dermatological systems. Understanding of pathophysiology and population risk has evolved, although most of the data available are still on older generation antiseizure medications such as phenytoin, carbamazepine, and valproic acid. The enzyme-inducing properties of some antiseizure medications make their effects on cardiovascular risk and bone health detrimental. Few clear guidelines exist for monitoring long-term effects of medication therapy for epilepsy. When selecting an antiseizure medication, consideration should be given to the individual patient's risks of adverse consequences on other organ systems. During monitoring of patients on chronic therapy, screening tools such as metabolic panels and bone density measurements can help stratify risk and guide management.



Publication History

Accepted Manuscript online:
10 October 2022

Article published online:
17 November 2022

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  • References

  • 1 Gloss D, Pargeon K, Pack A. et al; AAN Guideline Subcommittee. Antiseizure medication withdrawal in seizure-free patients: practice advisory update summary: report of the AAN Guideline Subcommittee. Neurology 2021; 97 (23) 1072-1081
  • 2 De Marcos FA, Ghizoni E, Kobayashi E, Li LM, Cendes F. Cerebellar volume and long-term use of phenytoin. Seizure 2003; 12 (05) 312-315
  • 3 Twardowschy CA, Werneck LC, Scola RH, Borgio JG, De Paola L, Silvado C. The role of CYP2C9 polymorphisms in phenytoin-related cerebellar atrophy. Seizure 2013; 22 (03) 194-197
  • 4 Shanmugarajah PD, Hoggard N, Aeschlimann DP. et al. Phenytoin-related ataxia in patients with epilepsy: clinical and radiological characteristics. Seizure 2018; 56: 26-30
  • 5 Algahtani H, Shirah B, Alqahtani AJ, Al-Malki AQ. Irreversible cerebellar atrophy as a complication of short-term phenytoin exposure: clinical improvement following discontinuation of the culprit. J Epilepsy Res 2020; 10 (02) 96-99
  • 6 Shorvon SD, Reynolds EH. Anticonvulsant peripheral neuropathy: a clinical and electrophysiological study of patients on single drug treatment with phenytoin, carbamazepine or barbiturates. J Neurol Neurosurg Psychiatry 1982; 45 (07) 620-626
  • 7 Boylu E, Domaç FM, Misirli H, Senol MG, Saraçoğlu M. Effects of the antiepileptic drugs on peripheral nerve function. Acta Neurol Scand 2010; 121 (01) 7-10
  • 8 Reimers A. New antiepileptic drugs and women. Seizure 2014; 23 (08) 585-591
  • 9 Hamed SA, Hamed EA, Kandil MR, El-Shereef HK, Abdellah MM, Omar H. Serum thyroid hormone balance and lipid profile in patients with epilepsy. Epilepsy Res 2005; 66 (1-3): 173-183
  • 10 Shi KL, Guo JX, Zhao HM. et al. The effect of levetiracetam and oxcarbazepine monotherapy on thyroid hormones and bone metabolism in children with epilepsy: a prospective study. Epilepsy Behav 2020; 113: 107555
  • 11 Zhang YX, Shen CH, Lai QL. et al. Effects of antiepileptic drug on thyroid hormones in patients with epilepsy: a meta-analysis. Seizure 2016; 35: 72-79
  • 12 Lopinto-Khoury C, Mintzer S. Antiepileptic drugs and markers of vascular risk. Curr Treat Options Neurol 2010; 12 (04) 300-308
  • 13 Josephson CB, Wiebe S, Delgado-Garcia G. et al. Association of enzyme-inducing antiseizure drug use with long-term cardiovascular disease. JAMA Neurol 2021; 78 (11) 1367-1374
  • 14 Zack M, Luncheon C. Adults with an epilepsy history, notably those 45-64 years old or at the lowest income levels, more often report heart disease than adults without an epilepsy history. Epilepsy Behav 2018; 86: 208-210
  • 15 Verrier RL, Pang TD, Nearing BD, Schachter SC. The epileptic heart: concept and clinical evidence. Epilepsy Behav 2020; 105: 106946
  • 16 Elliott JO, Jacobson MP, Haneef Z. Cardiovascular risk factors and homocysteine in epilepsy. Epilepsy Res 2007; 76 (2-3): 113-123
  • 17 Mintzer S, Yi M, Hegarty S, Maio V, Keith S. Hyperlipidemia in patients newly treated with anticonvulsants: a population study. Epilepsia 2020; 61 (02) 259-266
  • 18 Vyas MV, Davidson BA, Escalaya L, Costella J, Saposnik G, Burneo JG. Antiepileptic drug use for treatment of epilepsy and dyslipidemia: systematic review. Epilepsy Res 2015; 113: 44-67
  • 19 Brämswig S, Kerksiek A, Sudhop T, Luers C, Von Bergmann K, Berthold HK. Carbamazepine increases atherogenic lipoproteins: mechanism of action in male adults. Am J Physiol Heart Circ Physiol 2002; 282 (02) H704-H716
  • 20 Mintzer S, Dimova S, Zhang Y. et al. Effects of lacosamide and carbamazepine on lipids in a randomized trial. Epilepsia 2020; 61 (12) 2696-2704
  • 21 Mintzer S, Trinka E, Kraemer G, Chervoneva I, Werhahn KJ. Impact of carbamazepine, lamotrigine, and levetiracetam on vascular risk markers and lipid-lowering agents in the elderly. Epilepsia 2018; 59 (10) 1899-1907
  • 22 Jaeri S, Islamiyah WR. The potential mechanisms of effect of valproic acid on lipid profiles: an updated review. J Epileptol 2018; 26 (1–2): 49-55
  • 23 Silvennoinen K, de Lange N, Zagaglia S. et al; EpiPGX Consortium. Comparative effectiveness of antiepileptic drugs in juvenile myoclonic epilepsy. Epilepsia Open 2019; 4 (03) 420-430
  • 24 Bano S, Zuberi NA, Alam SM. Correlation between hyperhomocysteinemia and common carotid artery intima media thickness in carbamazepine treated epileptic patients using ultrasonography. Pak J Med Sci 2017; 33 (05) 1205-1209
  • 25 El-Farahaty RM, El-Mitwalli A, Azzam H, Wasel Y, Elrakhawy MM, Hasaneen BM. Atherosclerotic effects of long-term old and new antiepileptic drugs monotherapy: a cross-sectional comparative study. J Child Neurol 2015; 30 (04) 451-457
  • 26 Reddy MN. Effect of anticonvulsant drugs on plasma total cholesterol, high-density lipoprotein cholesterol, and apolipoproteins A and B in children with epilepsy. Proc Soc Exp Biol Med 1985; 180 (02) 359-363
  • 27 Keenan N, Sadlier LG, Wiltshire E. Vascular function and risk factors in children with epilepsy: associations with sodium valproate and carbamazepine. Epilepsy Res 2014; 108 (06) 1087-1094
  • 28 Gerstner T, Woelfing C, Witsch M, Longin E, Bell N, König S. Capillary microscopy and hemorheology in children during antiepileptic monotherapy with carbamazepine and valproate. Seizure 2006; 15 (08) 606-609
  • 29 Lai Q, Shen C, Zheng Y, Zhang Y, Guo Y, Ding M. Effects of antiepileptic drugs on the carotid artery intima-media thickness in epileptic patients. J Clin Neurol 2017; 13 (04) 371-379
  • 30 Safarpour Lima B, Mohamadzadeh A, Dadras M, Mahdavi A, Mansouri B, Farazdaghi M. Carotid intima-media and epicardial adipose tissue thickness in adult patients with epilepsy taking anti-seizure medication and its long-term significance. Epilepsy Behav 2021; 125: 108432
  • 31 LeFevre ML. U.S. Preventive Services Task Force. Screening for asymptomatic carotid artery stenosis: U.S. Preventive Services Task Force recommendation statement. [published correction appears in Ann Intern Med. 2015 Feb 17;162(4):323] Ann Intern Med 2014; 161 (05) 356-362
  • 32 Ascherio A, Munger KL, White R. et al. Vitamin D as an early predictor of multiple sclerosis activity and progression. JAMA Neurol 2014; 71 (03) 306-314
  • 33 Bscheider M, Butcher EC. Vitamin D immunoregulation through dendritic cells. Immunology 2016; 148 (03) 227-236
  • 34 Behera S. Non calcaemic and non-osteogenic functions of vitamin D: a brief review. MOJ Anat Physiol 2018; 5 (01) DOI: 10.15406/mojap.2018.05.00157.
  • 35 Charoenngam N, Shirvani A, Holick MF. Vitamin D for skeletal and non-skeletal health: what we should know. J Clin Orthop Trauma 2019; 10 (06) 1082-1093
  • 36 Hahn TJ, Hendin BA, Scharp CR, Haddad Jr JG. Effect of chronic anticonvulsant therapy on serum 25-hydroxycalciferol levels in adults. N Engl J Med 1972; 287 (18) 900-904
  • 37 Teagarden DL, Meador KJ, Loring DW. Low vitamin D levels are common in patients with epilepsy. Epilepsy Res 2014; 108 (08) 1352-1356
  • 38 Gröber U. Common drugs as vitamin D disruptors. J Transl Sci 2020; 6: 2-4
  • 39 Gough H, Bissesar A, Goggin T. et al. Factors associated with the biochemical changes in vitamin D and calcium metabolism in institutionalized patients with epilepsy. Ir J Med Sci 1986; 155 (06) 181-189
  • 40 Mintzer S, Boppana P, Toguri J, DeSantis A. Vitamin D levels and bone turnover in epilepsy patients taking carbamazepine or oxcarbazepine. Epilepsia 2006; 47 (03) 510-515
  • 41 Kumandas S, Koklu E, Gümüs H. et al. Effect of carbamazepine and valproic acid on bone mineral density, IGF-I and IGFBP-3. J Pediatr Endocrinol Metab 2006; 19 (04) 529-534
  • 42 Hoikka V, Alhava EM, Karjalainen P. et al. Carbamazepine and bone mineral metabolism. Acta Neurol Scand 1984; 70 (02) 77-80
  • 43 Turan MI, Cayir A, Ozden O, Tan H. An examination of the mutual effects of valproic acid, carbamazepine, and phenobarbital on 25-hydroxyvitamin D levels and thyroid function tests. Neuropediatrics 2014; 45 (01) 16-21
  • 44 LoPinto-Khoury C, Brennan L, Mintzer S. Impact of carbamazepine on vitamin D levels: a meta-analysis. Epilepsy Res 2021; 178: 106829
  • 45 Pitetzis DA, Spilioti MG, Yovos JG, Yavropoulou MP. The effect of VPA on bone: From clinical studies to cell cultures - the molecular mechanisms revisited. Seizure 2017; 48: 36-43
  • 46 Abdullah AT, Mousheer ZT. Vitamin D status in epileptic children on valproic acid; a case-control study. Arch Acad Emerg Med 2020; 8 (01) e13
  • 47 Fan D, Miao J, Fan X, Wang Q, Sun M. Effects of valproic acid on bone mineral density and bone metabolism: a meta-analysis. Seizure 2019; 73: 56-63
  • 48 Keith DA, Gallop PM. Phenytoin, hemorrhage, skeletal defects and vitamin K in the newborn. Med Hypotheses 1979; 5 (12) 1347-1351
  • 49 Harden CL, Pennell PB, Koppel BS. et al; American Academy of Neurology, American Epilepsy Society. Management issues for women with epilepsy–focus on pregnancy (an evidence-based review): III. Vitamin K, folic acid, blood levels, and breast-feeding: report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Epilepsia 2009; 50 (05) 1247-1255
  • 50 Pack AM, Morrell MJ. Epilepsy and bone health in adults. Epilepsy Behav 2004; 5 (Suppl. 02) S24-S29
  • 51 Baddoo DR, Mills AA, Kullab RB. et al. Metabolic bone disease in patients with epilepsy and the use of antiepileptic drugs - insight from a Danish cross-sectional study. Seizure 2021; 86: 29-34
  • 52 Kanda J, Izumo N, Kobayashi Y. et al. Effects of the antiepileptic drugs topiramate and lamotrigine on bone metabolism in rats. Biomed Res 2017; 38 (05) 297-305
  • 53 Heo K, Rhee Y, Lee HW. et al. The effect of topiramate monotherapy on bone mineral density and markers of bone and mineral metabolism in premenopausal women with epilepsy. Epilepsia 2011; 52 (10) 1884-1889
  • 54 Koo DL, Nam H. Effects of zonisamide monotherapy on bone health in drug-naive epileptic patients. Epilepsia 2020; 61 (10) 2142-2149
  • 55 Guo Y, Lin Z, Huang Y, Yu L. Effects of valproate, lamotrigine, and levetiracetam monotherapy on bone health in newly diagnosed adult patients with epilepsy. Epilepsy Behav 2020; 113: 107489
  • 56 Phabphal K, Geater A, Limapichat K, Sathirapanya P, Setthawatcharawanich S, Leelawattana R. Effect of switching hepatic enzyme-inducer antiepileptic drug to levetiracetam on bone mineral density, 25 hydroxyvitamin D, and parathyroid hormone in young adult patients with epilepsy. Epilepsia 2013; 54 (06) e94-e98
  • 57 Viswanathan M, Reddy S, Berkman N. et al. Screening to Prevent Osteoporotic Fractures: An Evidence Review for the U.S. Preventive Services Task Force [Internet]. Rockville, MD: Agency for Healthcare Research and Quality (US); 2018. (Evidence Synthesis, No. 162.) Table 1, Recommendations about Screening and Treatment of Osteoporosis from Various Professional and Health Organizations. Accessed October 10, 2022 at: https://www.ncbi.nlm.nih.gov/books/NBK532080/table/table1/
  • 58 Miller AS, Ferastraoaru V, Tabatabaie V, Gitlevich TR, Spiegel R, Haut SR. Are we responding effectively to bone mineral density loss and fracture risks in people with epilepsy?. Epilepsia Open 2020; 5 (02) 240-247
  • 59 Gandhi S, McArthur E, Mamdani MM. et al. Antiepileptic drugs and hyponatremia in older adults: two population-based cohort studies. Epilepsia 2016; 57 (12) 2067-2079
  • 60 Kim YS, Kim DW, Jung KH. et al. Frequency of and risk factors for oxcarbazepine-induced severe and symptomatic hyponatremia. Seizure 2014; 23 (03) 208-212
  • 61 Radeef MY, Al-Shamma K, Mohammed B. The effect of treatment with antiepileptic drugs (carbamazepine, valproic acid, topiramate, and their combination) on lipid profile, C-reactive protein, and renal function in Iraqi epileptic patients. Tikrit J Pharm Sci 2013; 9 (01) 1-8
  • 62 Groeper K, McCann ME. Topiramate and metabolic acidosis: a case series and review of the literature. Paediatr Anaesth 2005; 15 (02) 167-170
  • 63 Maalouf NM, Langston JP, Van Ness PC, Moe OW, Sakhaee K. Nephrolithiasis in topiramate users. Urol Res 2011; 39 (04) 303-307
  • 64 Wroe S. Zonisamide and renal calculi in patients with epilepsy: how big an issue?. Curr Med Res Opin 2007; 23 (08) 1765-1773
  • 65 Welch BJ, Graybeal D, Moe OW, Maalouf NM, Sakhaee K. Biochemical and stone-risk profiles with topiramate treatment. Am J Kidney Dis 2006; 48 (04) 555-563
  • 66 Dell'Orto VG, Belotti EA, Goeggel-Simonetti B. et al. Metabolic disturbances and renal stone promotion on treatment with topiramate: a systematic review. Br J Clin Pharmacol 2014; 77 (06) 958-964
  • 67 Jhagroo RA, Wertheim ML, Penniston KL. Alkali replacement raises urinary citrate excretion in patients with topiramate-induced hypocitraturia. Br J Clin Pharmacol 2016; 81 (01) 131-136
  • 68 Verrotti A, Scaparrotta A, Grosso S, Chiarelli F, Coppola G. Anticonvulsant drugs and hematological disease. Neurol Sci 2014; 35 (07) 983-993
  • 69 Mackay FJ, Wilton LV, Pearce GL, Freemantle SN, Mann RD. Safety of long-term lamotrigine in epilepsy. Epilepsia 1997; 38 (08) 881-886
  • 70 Lheureux PE, Hantson P. Carnitine in the treatment of valproic acid-induced toxicity. Clin Toxicol (Phila) 2009; 47 (02) 101-111
  • 71 Björnsson E. Hepatotoxicity associated with antiepileptic drugs. Acta Neurol Scand 2008; 118 (05) 281-290
  • 72 Sunwoo JS, Byun JI, Lee SK. A case of lacosamide-induced hepatotoxicity. Int J Clin Pharmacol Ther 2015; 53 (06) 471-473
  • 73 Asadi-Pooya AA, Rostaminejad M, Zeraatpisheh Z, Mirzaei Damabi N. Cosmetic adverse effects of antiseizure medications; a systematic review. Seizure 2021; 91: 9-21
  • 74 Gunturu LN. Case report on phenytoin-induced iatrogenic gingival hyperplasia. Asian J Pharm Clin Res 2020; 13 (10) 1-2
  • 75 SK Life Science, Inc. Xcopri (cenobamate) [package insert]. U.S. Food and Drug Administration website. Accessed January 25, 2022 at: www.accessdata.fda.gov/drugsatfda_docs/label/2019/212839s000lbl.pdf. Revised November 2019
  • 76 Greenwich Biosciences, Inc. Epidiolex (cannabidiol) [package insert]. U.S. Food and Drug Administration website. Accessed January 25, 2022 at: www.accessdata.fda.gov/drugsatfda_docs/label/2018/210365lbl.pdf. Revised June 2018
  • 77 Lundbeck. Onfi (clobazam) [package insert]. U.S. Food and Drug Administration website. Accessed January 25, 2022 at: www.accessdata.fda.gov/drugsatfda_docs/label/2016/202067s004lbl.pdf. Revised December 2016